section name header

Info


A. Characteristics navigator

  1. Biological warning system, activated in times of potential dangers
  2. Components
    1. Cognitive-affective
    2. Somatic
    3. Hyperarousal
    4. Behavioral
  3. Clinical Anxiety
    1. Generalized anxiety disorder (GAD; anxiety for >6 months): 10-15% of population
    2. Panic Disorder (intermittent) occurs in ~3% of population
    3. Phobias (intermittent) - social anxiety disorder (SAD, social phobia), specific phobias
    4. Adjustment Disorder with Anxious Mood
    5. Post-Traumatic Stress Disorder (PTSD)
    6. Agitated Depression (versus hypomania)
    7. Obsessive-compulsive disorder (OCD)
    8. Subtypes of clinical anxiety often co-exist
    9. Depression may be present in up to ~50% of patients with anxiety disorder
  4. Simple Phobias
    1. Anxiety reactions to conditions known to be harmless
    2. People usually avoid these situations
    3. Treatment, if necessary, is desensitization
  5. Etiology
    1. Unclear but appears related to hippocampal and hypothalamic supersensitivity
    2. Serotonin 1 receptors (HT-1R) and GABA-A receptor alpha-2 subunits appear involved
    3. Agents specific to GABA-A receptor alpha-2 subunits may have improved efficacy
  6. Screening (PRIME-MD)
    1. Primary Care Evaluation of Mental Disorders
    2. Completed by patients in primary care setting
    3. For screening depressive, anxiety, alcohol, somatoform, and eating disorders
    4. Self administered version is very effective, sensitive, and does not require clinician
    5. Based on results of PRIME-MD, clinician can focus discussion
  7. Two questions can cover anxiety screening as well as more complex screens (GAD-2) [6]
  8. Prevalence of Anxiety Disorders in Primary Care [6]
    1. GAD: 6.8% prevalence
    2. PTSD: 7.6% prevalence
    3. Panic disorder 6.8% prevalence
    4. Social anxiety disorder: 6.2% prevalence
  9. Cigarette smoking associated with 5-15 fold increased risk of various anxiety disorders [3]
  10. Effects of Chronic Anxiety and Stress on Peptic Ulcer Disease [4]
    1. Chronic psychological stress may also contribute to ulcerogenesis
    2. Psychological stress may increase acid production and/or reduce neutralization

B. Generalized Anxiety Disorder (GAD) [1,2]navigator

  1. Lifetime prevalence of ~5%
    1. Persistent, chronic disorder
    2. Patient has unfocused worry and anxiety, not connected to recent stressful events
    3. More common in women than men (~2:1)
    4. Psychiatric and somatic symptoms
    5. Feelings of threat, restlessness, irritability, tension
    6. Sleep disturbance (mainly insomnia), palpitations, dry mouth, sweating
  2. Risk Factors
    1. Family history of GAD
    2. History of physical or emotional trauma
    3. Apparent increased risk in diabetics (14% GAD in diabetics)
    4. Associated with smoking
    5. GAD is 5-6X more prevalent in adolescents who smoke heavily than nonsmokers
  3. Diagnostic Criteria (American Psychiatric Association)
    1. Excessive anxiety and worry occurring more days than not for >6 months, about a number of events or activities such as work or school performance
    2. Difficulty in controlling worry, concentrating, or making mind go blank
    3. Anxiety and worry assocated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, diffulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance
    4. Focus of anxiety and worry is not confined to features of other type of
  4. Coexisting Conditions
    1. Occur in ~65% of patients with GAD
    2. Major depression in ~60%
    3. Panic disorder in ~25%
    4. Alcohol abuse in ~35%
    5. Increased overall use of medical resources
    6. Coexisting diseases associated with poorer response to treatment

C. Differential Diagnosis [1] navigator

  1. Affective Symptoms
    1. Agitated Depression
    2. Hypomania
    3. Other anxiety disorders (as above)
  2. Delirium
  3. Psychosis: Depression, Hypomania, Agitation
  4. Central Nervous System Disorders
    1. Migraine
    2. Neoplasm
    3. Dementia
    4. Partial complex seizures
  5. Cardiovascular: angina, arrhythmia, mitral valve prolapse
  6. Hypoxia (acute and chronic)
  7. Endocrine
    1. Hyperthyroidism - should be evaluated in all new patients with anxiety disorder
    2. Cushing's Syndrome
    3. Carcinoid Syndrome
    4. Acute intermittent porphyria

D. Therapy for Generalized Anxiety Disorder [1,2,13]navigator

  1. In general, pharmacologic therapy is highly preferred
    1. Agents (benzodiazepines) with rapid onset of action should be given initially
    2. Agents with long term tolerability should be started early
    3. Benzodiazepines should be used only acutely and for short term management [19]
    4. Psychological therapy should be considered adjunctive
  2. Pharmacological
    1. For moderate to severe GAD, initially combine a benzodiazepine and an SSRI
    2. Benzodiazapines - use should be restricted to short term, acute administration [19]
    3. Anti-depressants (SSRI and SNRI) - SSRI agents now used first line over tricyclic agents
    4. Buspirone (Buspar®) - slow onset of action but few side effects, well tolerated
  3. Benzodiazepines [19]
    1. Use should be restricted to short term, initial therapy with SSRIs or other agents
    2. May also be used for acute exacerbations
    3. Cause withdrawal symptoms, abuse, cognitive impairment, sedation
    4. Benzodiazepines are slowly tapered over <4 weeks as SSRI's take effect
    5. Suggested doses are provided below; start at lower doses
    6. Alprazolam (Xanax®): available in short (tid-qid) or long (bid XR) acting forms
    7. Lorazepam (Ativan®): 0.5-2mg q6-8 hours prn
    8. Clonazepam (Klonopin®): 0.25mg bid slowly titrate up; max 4mg daily divided
    9. Diazepam (Valium®) is not recommended due to it's long half-life
    10. Imipramine or buspirone facilitate discontinuation of long-term benzodiazepines [17]
  4. Selective Serotonin and Mixed Reuptake Inhibitors (SSRI, SNRI)
    1. Some SSRI's, particularly fluoxetine (Prozac®), cause an increase in anxiety
    2. Paroxetine (Paxil®), escitalopram (Lexapro®), venlafaxine XR (Effexor®), duloxetine (Cymbalta®) are FDA approved for GAD as well as depression
    3. Paroxetine 20mg initially or escitalopram 10mg initially, usually doubling dose
    4. Venlafaxine is an SNRI; dose 75-225mg po qd effective within 1-2 weeks for 28 weeks [14]
    5. SSRI or SNRI dose is gradually increased and often used as monotherapy
    6. Fluvoxamine is effective for children and adolescents with GAD, social anxiety, and separation anxiety disorder [15]
    7. Caution with SSRI or SNRIs in children and adolescents with depression [16]
    8. Many of these agents are also effective therapy for social anxiety disorder (see below)
  5. Buspirone (Buspar®)
    1. Serotonergic 5HT-1A receptor agonist anxiolytic agent
    2. Generally very well tolerated if dose is escalated slowly
    3. Dose is initially 5mg po bid-tid, increase by 5mg per dose every 3-4 days
    4. Target dose is 20-30mg po bid as tolerated
    5. Generally requires at least 4-6 weeks for onset of action and often added on to SSRIs
  6. Psychological
    1. Cognitive behavioral therapy (CBT) - as effective as most pharmacotherapies [2]
    2. Psychotherapy
    3. Relaxation (including biofeedback)
    4. Group Encounters
  7. Psychotherapy
    1. Directive - therapist directs insight into difficulties and directs solutions
    2. Nondirective - patients define difficulties and achieve their own solutions
    3. Psychotherapy (nondirective) delivered by therapist and general practitioner equally effective on most scales
    4. In general, patients prefer psychotherapy delivered by therapist
  8. Efficacy
    1. Medications (benzodiazepines, SSRIs) are nearly always more effective than CBT acutely
    2. CBT and medications are of similar efficacy in subacute short term
    3. These therapies are about equally effective in the long term
  9. Novel Therapeutics
    1. Substance P (neurokinin 1) inhibitor MK-869 has shown some efficacy
    2. Neuropeptide Y receptor Agonists
    3. Glycine Site Antagonists
    4. Cholecystokinin-B receptor antagonists
  10. Severe patients may become suicidal and this must be evaluated

E. Panic Disorder (Panic Attacks) [20,21]navigator

  1. Epidemiology
    1. ~2% of adults in community
    2. ~5% of persons seen by primary care physicians
    3. Female to male 2:1
    4. Bimodal distribution age of onset: one peak in late adolescence, the other in mid-30s
  2. Etiology
    1. May be mediated through serotonin receptors
    2. Serotonin Receptors 1A and 2 may inhibit anxiety
    3. Type 1B may mediate anxiogenesis
    4. More than 15X risk of developing panic attacks associated with cigarette smoking [3]
    5. Elevated sympathetic nervous system activity documented during attacks [5]
  3. Symptoms
    1. Sympathetic: dyspnea, palpitations, chest discomfort (even real pain), diaphoresis
    2. Chest pain may be severe and even mistaken for cardiac pain
    3. Feelings: Smothered, Unusual feelings ("unreality")
    4. Fear of dying, or losing control, and agorophobia often accompany attacks
    5. Attacks last seconds to hours, are paroxysmal, and often occur "out of the blue"
  4. Associated Findings
    1. Agorophobia - fear of being without people (such as separation anxiety, usually children)
    2. Genetic component present - separation anxiety as child may play a role
    3. Possible linkage to Mitral Valve Prolapse
    4. Multiple chemical sensitivity may be an anxiety reaction
  5. Criteria for Diagnosis of Panic Disorder (DSM-IV)
    1. Recurrent, unexpected panic attack
    2. Panic attack defined as discrete period of intense fear or discomfort in which at least four of the following symptoms (c) develop abruptly and reach a peak within 10 minutes:
    3. Palpitations (pounding heart), sweating, trembling or shaking, shortness of breath, feeling of choking, chest pain or discomfort, nausea or abdominal distress, feeling dizzy or lightheaded or faint, derealization or depersonalization, feer of losing control or going crazy, fear of dying, chills or hot flushes, paresthesias
    4. At least one of the attacks followed by at least one month of at least one of the following:
    5. Persistent concern about having additional attacks
      1. Worry about the implications of the attack or its consequences
      2. Clinically significant change in behavior related to the attacks
    6. Panic attacks not due to direct physiological effects of an illicit substance, or a prescription medication, or a general medical condition (such as hyperthyroidism)
    7. Panic attacks not better accounted for by another mental disorder such as:
    8. Social phobia - on expsoure to a feared social situation
      1. Specific phobia - during expsoure to a specific situation that prompts phobic response
      2. Post-traumatic stress disorder (PTSD) - see below
      3. Separation anxiety disorder - in response to being away from home or close relative
  6. Treatment Overview [21,23]
    1. Critical to review diagnosis with patient and reassure concerning medical symptoms
    2. >80% of patients are fearful of having a serious medical condition such as heart attack
    3. CBT is likely as effective as pharmacologic agents and is underutilized in USA [21]
    4. Five classes of agents have shown efficacy superior to placebo: SSRI, SNRI, TCA, benzodiazepines (BZD), monoamine oxidase inhibitors
    5. SSRI, TCA and BZD show similar efficacy on lobal anxiety symptoms (frequency of panic attacks, agoraphobia); SSRI and TCA had better efficacy than BZD on depression symptoms
    6. SSRI are recommended as first line; fluoxetine, sertraline, paroxetine are FDA approved for panic disorder and venlafaxine XR has shown activity
    7. Benzodiazepines are best used for acute and short term treatment and can be added to SSRIs for short term (2-4 weeks) control
    8. Initially, combination of benzodiazepines and SSRI are probably the most effective [8]
    9. Thus, sertraline (Zoloft®) 50-100mg qd + clonazepam 0.5mg tid are good initial therapy [8]
    10. Alprazolam extended release (Xanax XR®) is approved for once daily dosing for panic attacks but is only modestly effective [7]
    11. After 2-4 weeks, the benzodiazepine can be tapered off
    12. CBT may be longer-lasting than medications; effects remain when CBT is discontinued [21]
  7. Other Agents [23]
    1. ß-adrenergic blockers for sympathetic symptoms only
    2. If sleep is disturbed, or with agitation, consider trazodone (Desyryl®)
    3. Zolpidem (Ambien®) or eszopiclone (Lunesta®) for insomnia
    4. High rate of relapse (~75%) within 1 year of discontinuing agents
    5. Buspirone (partial agonist of serotonin 1A receptors) 10-20mg po tid may be effective

F. Social Anxiety Disorder (SAD, Social Phobias) [18,22] navigator

  1. Fears associated with situations in which a person feels exposed to scrutiny by others
  2. Epidemiology
    1. Lifetime prevalence ~12%
    2. Usually begins in teenage years (20% by age 11; 80% by age 20)
    3. Typically chronic
    4. Usually occurs in persons who with generalized anxiety disorder
  3. Symptoms
    1. Most patients have generalized fears of any social interaction
    2. Minority of patients have fears of specific situations such as public speaking
  4. DSM-IV Criteria (Panel 1, Ref [18])
    1. Notable and persistent fear of at least one social performance situations with exposure to unfamiliar people or possible scrutiny by others
    2. Person fears that he/she will act in a way (or show symptoms of anxiety) that will be humiliating or embarrassing
    3. Exposure to feared social situation almost invariably provokes anxiety, which can take the form of a panic attack
    4. Person recognizes that fear is excessive or unreasonable
    5. Feared social or performance situations are avoided or endured with intense anxiety or distress
    6. Condition interferes substantially with the person's normal routine, occupational (or academic) functioning, or social activities or relationships, or have notable distress about having phobia
    7. Fear or avoidance is not due to direct physiological effects of a substance or general medical condition, and is not accounted for by another mental disorder
    8. If a general medical condition or another mental disorder is present, the social or perforance fear is unrelated ot it
    9. Specify the disorder as generalized if fears include most social situations
  5. Treatment
    1. Initially with cognitive behavioral therapy (CBT) and/or pharmacotherapy
    2. CBT shows marked benefit in 50-70% of patients
  6. Pharmacologic Therapy
    1. Fluvoxamine (Fluvox®), an SSRI, reduces symptoms of social phobia
    2. Paroxetine (Paxil®), another SSRI, clearly reduces symptoms of social phobia [9]
    3. Venlafaxine (Effexor®), an SNRI, shows benefit in SAD and other anxiety syndromes
    4. Escitalopram (Lexapro®), improved symptoms
    5. SSRIs or SNRIs are used for at least 8-12 weeks (25% more response at 12 versus 8 weeks)
    6. Fluoxetine (Prozac®) should be avoided
    7. Benzodiazepines are second or third line

G. Post-Traumatic Stress Disorder (PTSD) [10,11,12]navigator

  1. Originally believed to apply only to soldiers in combat
  2. Now, often diagnosed in civilians involved in a traumatic event:
    1. Natural disasters
    2. Physical assault, particularly sexual (rape)
    3. Fire
    4. Motor vehicle and other serious trauma
    5. Displacement as refugee
    6. Witnessing inflicted injury or death
  3. Clinical Presentation
    1. Re-experiencing the events (nightmares, intrusive thoughts, flashbacks, memories)
    2. Phobic avoidance of trauma-related situations and memories
    3. Emotional numbing and avoidance (flattened affect, detachment, loss of motivation)
    4. Increased arousal (includes startle reactions, poor concentration, hypervigilance concerning safety, difficulty falling or staying asleep)
    5. Symptoms must be present for at least one month
    6. This disorder must cause clinically significant distress or impaired functioning
  4. Associated with Increased Risk For:
    1. Anxiety
    2. Depression
    3. Alcohol or substance abuse disorders
  5. Survivors of childhood abuse have increased rates of:
    1. Smoking and associated pulmonary disease
    2. Sexually transmitted disease
    3. Severe obesity
    4. Ischemic heart disease
    5. Cancer
    6. Fractures
    7. Liver disease (likely related to alcohol abuse)
  6. Pathophysiology
    1. Unclear why certain people recover from traumatic events and others do not
    2. Chronic PTSD patients have increased norepinephrine and alpha2-adrenergic receptors
    3. Thyroid hormone levels increased in PTSD
    4. Increased trauma reactivity in amygdala and hippocampus on physiologic imaging
    5. Sensitivity of negative-feedback system of hypothalamic-pituitary-adrenal axis increased
    6. Development of PTSD likely facilitated by failure to contain biologic stress-response at the time of trauma
  7. Treatment Requires Accurate Diagnosis [10]
    1. Medical therapy is now first line
    2. Psychosocial treatments are also effective in many PTSD situations
    3. Combination medical and psychosocial therapy is more effective than single modality
    4. Non-SSRI drugs are now considered second line
    5. Striking balance between between focus on heroism and resilience versus victimhood and pathological change is critical [11]
  8. Serotonin Selective Reuptake Inhibitors (SSRIs)
    1. Sertraline (Zoloft®) 50-200mg/day effective in 53% of patients versus 32% for placebo
    2. Paroxetine (Paxil®) also approved by FDA for PTSD
    3. Fluoxetine (Prozac®) has been shown to be effective after 12 weeks
    4. If no response to any of these SSRIs at 8 weeks, then switch to mixed reuptake inhibitor
  9. Mixed Reuptake Inhibitors
    1. Nefazone (Serzone®)
    2. Venlafaxine (Efffexor®)
  10. Mood stabilizer such as valproate (Depakote®) can be added when partial responses seen
  11. Avoid benzodiazepines as these are not effective and often cause dependence in PTSD

References navigator

  1. Fricchione G. 2004. NEJM. 351(7):675 abstract
  2. Tyrer P and Baldwin D. 2006. Lancet. 368(9553):2156 abstract
  3. Johnson JG, Cohen PC, Pine DS, et al. 2000. JAMA. 356(9239):2348
  4. Levenstein S, Ackerman S, Kiecolt-Glasser JK, Dubois A. 1999. JAMA. 281(1):10 abstract
  5. Goldstein DS, Robertson D, Esler M, et al. 2002. Ann Intern Med. 137(9):753 abstract
  6. Kroenke K, Spitzer RL, Williams JB, et al. 2007. Ann Intern Med. 146(5):317 abstract
  7. Alprazolam Extended Release. 2003. Med Let. 45(1157):43
  8. Goddard AW, Brouette T, Almai A, et al. 2001. Arch Gen Psychiatry. 58:681 abstract
  9. Baldwin D, Bobes J, Stein DJ, et al. 1999. Br J Psychiatry. 175:120 abstract
  10. Stein MB. 2002. JAMA. 288(12):1513 abstract
  11. Stein DJ, Seedat S, Iversen A, Weswsely S. 2007. Lancet. 369(9556):139 abstract
  12. Yehuda R. 2002. NEJM. 346(7):108
  13. Drugs for Depression and Anxiety. 1999. Med Let. 341(1050):33
  14. Gelenberg AJ, Lydiard RB, Rudolph RL, et al. 2000. JAMA. 283(23):3082 abstract
  15. Pediatric Psychopharmacology Anxiety Study Group. 2001. NEJM. 344(17):1279 abstract
  16. Treatment for Adolescents with Depression Study Team. 2004. JAMA. 292(7):807 abstract
  17. Richels K, DeMartinis N, Garcia-Espana F, et al. 2000. Am J Psychiatry. 157:1973 abstract
  18. Stein MB and Stein DJ. 2008. Lancet. 371(9618):1115 abstract
  19. Alprazolam. 2005. Med Let. 47(1200):5 abstract
  20. Katon WJ. 2006. NEJM. 354(22):2360 abstract
  21. Roy-Byrne PP, Craske MG, Stein MB. 2006. Lancet. 268(9540):1023
  22. Schneier FR. 2006. NEJM. 355(10:1029 abstract
  23. Drugs for Anxiety. 1997. Med Let. 39(998):33 abstract